Prostate cancer is the most prevalent cancer and is the second major cause of cancer-related deaths among American men. However, little is known about the etiology of prostate cancer and the risk factors for advanced disease. Recently, dietary influences that may alter methylation patterns in DNA have been implicated in the etiology of various cancers. However, few investigators have examined the relationship between DNA methylation and genotypes that may be associated with prostate cancer. The objective of this proposal is to explore the potential relationship between prostate cancer and the major genes affecting DNA methylation through folate metabolism pathways. We hypothesize (1) that both biological and environmental factors influence prostate cancer onset in sporadic cases and (2) that ethnic/cultural differences in these factors may explain racial differences in patterns of disease. The overall aim of this study is to use novel analytical methods to determine whether common variants in select one- carbon metabolizing genes modify the risk of sporadic prostate cancer in a diverse population. The presence of an association may help to identify the course of disease progression and the individuals who are most likely to develop prostate cancer and progress the quickest. The effect of folate on prostate cancer occurrence is likely to involve interactions of genes at various loci and environmental exposures. Therefore, simultaneous consideration of multiple predictors in the context of a carefully designed epidemiologic study is important. The genes to be studied in this research include MTHFR, CBS, MS, MSRR, TS, and SHMT. Novel analytical methods, including CART, haplotype analysis, and trimming and weighting, will be explored. An ongoing currently funded hospital-based case-control study design will be used to accomplish the following three specific aims: (1) To determine the frequencies of genotypes associated with folate metabolism by race/ethnicity;(2) To determine the association between prostate cancer and genotypes associated with one-carbon metabolism;(3) To determine the effect of folate intake and genotype on prostate cancer occurrence and progression.